Updates in Management of ITP from ASH

The American Society of Hematology (ASH) held its 50th annual meeting in San Francisco, California, on December 6-9, 2008. Attendance at this year’s conference was greater than in previous years, and results from several studies not only demonstrated progress in hematologic diseases but also marked the potential for immediate changes in clinical practice, including the treatment of immune thrombocytopenic purpura (ITP).

Currently, approximately 140,000 patients are being treated for chronic ITP in the United States and Europe. The treatment goal for the management of ITP is often to achieve a hemostatic platelet count in order to reduce the risk of bleeding events. Patients with ITP suffer antibody-mediated platelet destruction and inadequate platelet production resulting in dangerously low platelet levels.

Just recently, great strides in the progress of treatment for ITP have been made with the approval of two new agents: Nplate™ (romiplostim) and Promacta™ (eltrombopag), both thrombopoietin receptor agonists. These agents have demonstrated the ability to maintain platelet levels with a tolerable safety profile as well as potentially allowing for a reduction in other concurrent ITP therapies.

As in other diseases, research in ITP also continues to gain a greater understanding of the genetics associated with the development of ITP and associated outcomes of specific genetic or molecular markers.

Nplate™(romiplostim)

Nplate is the first thrombopoietin receptor agonist approved for ITP. A member of the TPO mimetic class, Nplate is an Fc-peptide fusion protein (peptibody) that activates intracellular transcriptional pathways leading to increased platelet production via the TPO receptor (also known as cMpl). The peptide portion of Nplate has no amino acid sequence homology to endogenous TPO, mitigating the risk for development of anti-Nplate antibodies that cross-react with endogenous TPO. Nplate is approved for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins or splenectomy. Nplate should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increases the risk for bleeding. Nplate should not be used in an attempt to normalize platelet counts.

Long-term interim data from an open-label extension study evaluating Nplate in adult patients with chronic ITP were presented at this year’s ASH, demonstrating the maintenance of platelet levels for up to four years. This study included 215 ITP patients who had completed a previous Nplate clinical trial and did not experience a significant change in medical history. The Nplate starting dose on the extension study was 1 ug/kg by subcutaneous injection and was adjusted to maintain a platelet count between 50,000 and 200,000 platelets per microliter. Approximately half of the patients switched to self-injection of Nplate once on the extension study.

Overall, 74% of patients achieved a platelet response (defined as a platelet count of more than 50,000 platelets per microliter and double the baseline platelet count).

Platelet counts greater than 50,000 platelets per microliter were sustained for at least 10 consecutive weeks in 77% of patients; for at least 25 consecutive weeks in 67% of patients; and for at least 52 consecutive weeks in 41% of patients.

The most common adverse events were headache (34%), contusion (32%), and fatigue (31%).

To date, Nplate has been associated with a tolerable safety profile, with further data regarding its long-term side effect profile presented at this year’s ASH.

Approximately 2% of patients in both the placebo and Nplate arms experienced some form of thrombosis, most of which occurred in patients with medical co-morbidities predisposing them to the condition.

Platelet levels were not associated with thrombosis.

Dr. Liebman presented data from an analysis including 229 patients with chronic ITP included in eight clinical trials evaluating Nplate safety. The average age of patients in these trials was 51 years, and nearly 60% were splenectomized. All patients had received at least one prior therapeutic regimen for ITP.

The most common adverse events associated with Nplate were headache, confusion, and fatigue.

Thrombotic events were not increased with the use of Nplate compared with placebo (p > 0.05).

Bleeding events were significantly reduced with the use of Nplate compare with placebo.

Taken together, safety analyses of Nplate demonstrate a tolerable safety profile, even during long-term use. Thrombotic events were not increased with the use of Nplate, regardless of platelet levels, and bleeding events continued to be significantly decreased compared with placebo. As historic standard therapies for ITP are associated with significant side effects, these results are particularly encouraging for patients with ITP.

Promacta™ (eltrombopag)

Promacta is a small molecule thrombopoietin (TPO) receptor agonist for oral administration; it interacts with the transmembrane domain of the TPO receptor (also known as cMpl) leading to increased platelet production. Promacta was recently approved (November, 2008) for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Promacta should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increases the risk for bleeding. Promacta should not be used in an attempt to normalize platelet counts.

The pivotal Phase III trial of Promacta used in the approval process was presented at this year’s ASH meeting. Because the approval of Promacta is so recent, its integration into clinical practice is hinging on data brought forth regarding its effectiveness and safety.

Results of the RAISE trial, a six-month, Phase III, double-blind, placebo-controlled trial comparing Promacta to placebo in chronic ITP were presented as a late-breaking abstract at this year’s ASH. The RAISE trial included 197 patients who had received prior therapy for ITP and had a platelet count of 30,000 or less at baseline. Half of the patients had platelet counts less than 15,000, half were receiving therapy for ITP, and 35% had been splenectomized. Treatment was to be carried out for six months. The median baseline platelet counts were 16,000 in both the Promacta (n=135) and placebo group (n-62). Patients were randomized to Promacta (50 mg once daily as an initial dose that could be titrated between 75 mg and 25 mg once daily or less frequently to match platelet responses) or placebo in a 2:1 fashion. The primary endpoint was the odds of responding compared to placebo (responses being defined as platelets between 50,000 and 400,000) during the treatment period.

Patients treated with Promacta were eight times more likely to respond than those on placebo (OR [95% CI] = 8.2 [4.32, 15.38] ;P<0.001).

Platelet counts never exceeded 30,000 in the placebo group.

Any bleeding and significant bleeding was significantly less in patients receiving Promacta (P <0.001).

Side effect profiles were not significantly different between the two treatment arms.

Splenectomy, baseline platelet counts, and other medications did not affect response to Promacta.

In the Promacta group, the median platelet count was 36,000 after the first week and ranged between 52 and 91,000 for the remainder of the study.

These authors concluded: “Eltrombopag was well-tolerated, with a similar safety profile to placebo, and is an important new treatment option for patients with chronic ITP.”

An open-label extension study of Promacta, referred to as the 207 EXTEND study, was available to patients who had participated in previous Promacta clinical trials. Sixty-nine patients participating in the open-label study were on concomitant medications at baseline.

33 patients were able to stop taking their concomitant medications or were able to reduce their intake at least temporarily while on Promacta.

Corticosteroids were the type of medication most frequently reduced or stopped.

Rescue therapy was not necessary in 23 of these patients.

Although platelet levels decreased slightly during reduction or stopping of concomitant medication, it was not statistically significant.

Efficacy of the EXTEND study was also presented, demonstrating continued effectiveness through 40 weeks of therapy with Promacta among 165 patients with ITP refractory or intolerant to standard therapies. Bleeding events were reduced by 50% compared with baseline, with over 80% of patients achieving clinical benefit. Two concerns of Promacta are liver toxicity (prompting the FDA to require a box warning on the label about this potential adverse effect) as well as reticular fibers in the bone marrow. However, no new safety concerns were reported from any of the recently presented trials.

These results indicate that Promacta is an effective agent in the treatment of ITP. Future trials directly comparing Promacta to other therapeutic regimens, such as Nplate, will help determine its true clinical efficacy for patients with chronic ITP.

Rituxan® (rituximab)

Prior uncontrolled trials have demonstrated activity of Rituxan® (rituximab) in ITP, particularly in refractory patients. Rituxan continues to be evaluated in several different diseases, including different forms of ITP. One of the plenary presentations at 2008 ASH included long-term data from a Phase III randomized trial comparing Rituxan plus dexamethasone with dexamethasone only in previously untreated ITP. The trial was randomized in a 1:1 fashion and conducted by Italian researchers from 2005 to 2007. Patients were randomized to either a single course of oral dexamethasone (40 mg on days 1-4) or dexamethasone (same dose schedule) plus Rituxan (375 mg/m2 IV on days 7, 14, 21, 28). Patients treated with dexamethasone only who failed to achieve a sustained response and had a platelet count ≤ 20 x 109/L (from day 30 up to the end of six months) could crossover to receive salvage therapy with dexamethasone plus Rituxan. The primary objective of the study was sustained response (SR), defined as a platelet count > 50 x 109/L six months following therapy. At baseline, all patients (n=101) had a platelet count of 20,000 109/L or less.

69% of patients receiving Rituxan achieved an initial platelet count of 50,000 or more compared with 31% in the dexamethasone alone group (p=0.009).

Platelet levels of 50,000 or greater were sustained in 85% of patients in the Rituxan group compared with 39% in the dexamethasone alone group (p <0.001).

Sustained platelet levels of 100,000 or greater were also greater in the Rituxan group (77%) than in the dexamethasone-alone group (37%) (p<0.001).

More than half of the patients receiving salvage Rituxan also responded.

Rituxan was not associated with an increase in toxicities.

The researchers concluded: “The long period of relapse free survival registered in some patients suggests a possible curative effect. This treatment can be offered as an option before splenectomy, particularly in those patients where the surgical option is not well accepted or have higher risk of complications.”

Genetics

As with most diseases, understanding potential genetic expression and mutations of ITP provides hope for a greater understanding and therefore prevention or improved treatment for patients with the disease. Approximately 80% of pediatric patients with ITP will never develop a chronic form of ITP, as their disease is self-limiting. Identifying the 20% of pediatric patients who will progress to chronic ITP would allow for early intervention and monitoring. Researchers from Stanford University recently conducted a study to explore genetic expression among pediatric patients with ITP. Sixteen children with acute phase of ITP had whole blood samples evaluated; seven of these patients subsequently developed chronic ITP. A cohort of five children who did not have ITP also had whole blood evaluated. Two genes, the VNN1 and the AVIL, were significantly over expressed among children who developed the chronic form of ITP compared with those whose ITP was self-limiting and those who did not have ITP. Although the authors stated that this information is intriguing and will some day undoubtedly provide important implications in the treatment of pediatric ITP, clinical applicability stemming from this information is not yet known as targeted therapies or preventive measures using overexpression of these genes are not yet available.

Conclusion

Novel agents such as Nplate and Promacta, as well as the potential integration of targeted agents such as Rituxan into treatment regimens for ITP, are providing patients with improved outcomes coupled with reduced toxicity compared with prior standard regimens. As data continue to emerge, uptake of these agents into the routine clinical care for patients with ITP will increase.

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